To　rationally　design　inhibitors　targeting　at　HIV-1　transmembrane　protein-gp41,　molecular　docking,　molecular　dynamic　(MD)　simulation　and　free　energy　calculation　are　adopted　to　explore　the　binding　mode　between　gp41　and　its　inhibitor　NB-2.　A　de　novo　drug　design　method　inhibitors　of　gp41,　and　two　main　binding　modes　between　NB-2　and　gp41　are　attained　by　molecular　docking.　The　results　obtained　with　MD　simulation　and　binding　energy　calculation　indicate　that　Mode　1　is　superior　to　another　and　is　proposed　to　be　the　rational　binding　mode.　Based　on　this　mode,　103　new　compounds　were　designed　and　evaluated　for　their　binding　affinities　into　gp41.　These　compounds　possess　structural　features　not　seen　in　known　HIV-1　gp41　inhibitors　and　most　of　them　bind　into　gp41　with　lower　binding　free　energy　than　NB-2.　The　binding　modes　reasonably　interpret　the　interactions　between　NB-2　and　gp41.